Methods and apparatuses for coating balloon catheters

ABSTRACT

Embodiments of the invention relate to a method and apparatus for coating a medical device. In one embodiment, the method for preparing a substantially uniform coated medical device includes (1) preparing a coating solution comprising a solvent, a therapeutic agent, and an additive; (2) loading a metering dispenser with the coating solution; (3) rotating the medical device about the longitudinal axis of the device and/or moving the medical device along the longitudinal or transverse axis of the device; (4) dispensing the coating solution from the metering dispenser onto a surface of the medical device and flowing the coating solution on the surface of the medical device while the medical device is rotating and/or linearly moving; and (5) evaporating the solvent, forming a substantially uniform coating layer on the medical device.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §119 ofU.S. Provisional Application No. 61/092,872, filed on Aug. 29, 2008, thedisclosure of which is incorporated by reference herein.

FIELD OF THE INVENTION

Embodiments of the present invention relate to methods for coatingmedical devices, and particularly for coating balloon catheters.Embodiments of the present invention also relate to apparatuses used forcoating these medical devices.

BACKGROUND OF THE INVENTION

It has become increasingly common to treat a variety of medicalconditions by introducing a drug releasing medical device into thevascular system. For example, medical devices used for the treatment ofvascular diseases include drug eluting stents. There is an increasingdemand for better coating methods to control the dose of therapeuticagent and to improve drug distribution and uniformity in the coatings ofthese medical devices.

Methods for coating a drug eluting stent (DES) have been developed inrecent years. The stent is coated with a polymer into which drug isimpregnated. Methods for coating drug eluting stents include dipping in,or spraying with, the coating solution or composition. The coatingcomposition often includes a solvent, a polymer dissolved in thesolvent, and a therapeutic agent dissolved or dispersed in the coatingcomposition. The composition is then applied to the stent by sprayingthe composition onto the stent or by dipping the stent in the coatingcomposition. The solvent is allowed to evaporate, leaving a coating ofthe polymer and therapeutic drug on the stent surfaces. These methodsare useful for coating discontinuous surfaces, such as that of a stent.The surfaces outside, inside, and in between struts of the stent can becoated by these methods. In both spraying and dipping coatings, theamount of coating transferred is not precisely controlled and has to beindependently quantified for dose verification. Most of the coating doesnot spray onto the medical device. Thus, the amount of the coating onthe medical device is less than the amount of coating that is sprayed.The amount of coating on the medical device in the dipping coatingdepends on solvent, solution, concentration, and adhesive property ofcoating to medical device. The dose or load of drug coated on the stentmay be controlled by weighing the stent after the coating is dried,since a stent is a small metal implant that can easily be placed on ascale. A precise balance can be used to measure the total dose of drugcoated on the device. An important limitation of these methods is thatthe drug dose cannot be controlled if the medical devices cannot beweighed precisely, or if the weight of the coating layer is negligiblerelative to the weight of the device, such as a balloon catheter. Aballoon catheter typically may be an assembly of long plastic tubes thatweighs, for example, approximately 10 to 20 grams. The weight of thedrug coating (typically 0.1 to 10 mg) is therefore well within themeasurement error of the weight of the balloon catheter itself.

Non-stent based local delivery systems, such as balloon catheters, havealso been effective in the treatment and prevention of restenosis. Theballoon is coated with an active agent, and when the blood vessel isdilated, the balloon is pressed against the vessel wall to deliver theactive agent.

The current method for drug coating of a balloon catheter is dipping orspraying. The coating layer formed by dipping or spraying is not uniformon the surface of the balloon, and the drug is not uniformly distributedin the coating layer overlying the balloon surface. Furthermore, thedose of the drug deployed on the device after dipping or spraying is notconsistent and in some cases may vary from as much as 0.5 to 11 μg/mm²,or as much as 300%, from balloon to balloon or from one region of theballoon surface to another. In the case of spray coating, large amountsof sprayed drug will not land on the surface of the balloon catheter andthe amount of the drug on the balloon catheter is less than the amountof drug sprayed. In the case of dip coating, it is also very difficultto load a large amount of drug on the balloon, even with multiple dips,because drug already on the balloon may dissolve away during subsequentdips. In both situations, sections of the device that are not desirableto coat must be masked.

Thus, there is still a need to develop an improved method and apparatusfor coating highly specialized medical devices. There is still a need todevelop improved methods for precisely measuring and controlling theconcentration or dose of drug on the surface of coated medical devices.There is a need that the amount of drug dispensed is the same as that onthe surface of the medical devices, especially balloon catheters.Furthermore, there is still a need to improve the uniformity of drugdistribution in the coating layer and the uniformity of the coating onthe surface of the medical device.

SUMMARY OF THE INVENTION

Embodiments of the present invention relate to methods and apparatusesfor drug coating the exterior surface of a medical device, for example,the inflatable portion of a balloon catheter or a medical device thathas a continuous surface. In one embodiment, the amount of the drug ispremetered before its dispensement. The amount of the dispensed drugfrom the coating apparatus is the same as or substantially the same asthat on the surface of the medical device after the coating processaccording to embodiments of the invention. The dispensed drug is appliedas a solution, dispersion, suspension, emulsion or other mixture that isdispensed in the form of a droplet or droplets or continuous flow thatthen flows on the surface of the medical device. The term “solution”includes a solution, dispersion, suspension, emulsion or other mixturein embodiments of the inventions. The flow of the solution or dispersioncomposition on the moving surface of the medical device produces auniform coating. In contrast to dipping or spraying coating methods,during the coating process of at least certain embodiments almost nosolution is lost. In certain embodiments, almost none of the solution islost during dispensing onto the surface of the medical device, and nodrug is lost while the solvent is evaporated as the coating solutionflows on the surface of the medical device. Therefore, the metered drugdose is the same as or substantially the same as the dose of the drug onthe surface of the medical device.

In one embodiment, the coating composition comprises a therapeuticagent, an additive, and a solvent. In another embodiment, the coatingcomposition comprises a therapeutic agent, a polymer, and a solvent. Inanother embodiment, the coating composition comprises a therapeuticagent, a hydrophilic molecule, and a solvent. In another embodiment, thecoating composition comprises two or more therapeutic agents, two ormore additives, and/or two or more solvents. In yet another embodiment,the coating composition comprises an additive and a solvent, but nodrug, for example, in a top coating layer that might be deployed usingthe methods of the present invention over a drug layer previously coatedon a medical device.

In one embodiment, the method for preparing a substantially uniformcoated medical device comprises (1) preparing a coating solutioncomprising a solvent, a therapeutic agent, and an additive; (2) loadinga metering dispenser with the coating solution; (3) rotating the medicaldevice about the longitudinal axis of the device and/or moving themedical device in a linear direction along the longitudinal ortransverse axis of the device; (4) dispensing the coating solution fromthe metering dispenser onto a surface of the medical device and flowingthe coating solution on the surface of the medical device while themedical device is rotating and/or linearly moving; and (5) evaporatingthe solvent, forming a coating layer on the surface of the medicaldevice.

In one embodiment, steps (2), (3), (4) and (5) occur concomitantly.

In one embodiment, steps (2), (3) (4) and (5) are repeated until atherapeutically effective amount of the therapeutic agent in the coatingsolution is deposited on the surface of the medical device.

In one embodiment, the medical device or a portion thereof has acontinuous surface.

In one embodiment, the method further comprises a step (6) drying themedical device, (7) sterilizing the medical device; and a step (8)drying the medical device after sterilization. In one embodiment, instep (7) the medical device is sterilized with ethylene oxide and instep (8), the medical device is dried under vacuum at about 5 to 45° C.for approximately 2 to 56 hours. In one embodiment, in step (8), themedical device is dried under vacuum at about 0 to 100° C. forapproximately 2 to 56 hours.

In an alternative embodiment, the medical device is fixed in place andthe metering dispenser dispenses the coating solution onto the surfaceof the medical device while the metering dispenser is rotating about thelongitudinal axis of the medical device and/or moving in a lineardirection along the longitudinal or transverse axis of the medicaldevice. In another alternative embodiment, the metering dispenserdispenses the coating solution onto the surface of the medical devicewhile each of the metering dispenser and the medical device are rotatingabout the longitudinal axis of the medical device and/or moving in alinear direction along the longitudinal or transverse axis of themedical device.

In one embodiment, in step (5), the solvent is evaporated while thecoating solution is moving at uniform speed, forming a substantiallyuniform dry coating layer over the surface of the medical device.

In one embodiment, all of the metered coating solution is deployed onthe device, which allows for quantifying, without need for weighing, thedrug dose in the coating layer overlying the device.

In one embodiment the medical device is a balloon catheter, and themethod for preparing a substantially uniform coated balloon cathetercomprises (1) preparing a coating solution comprising a solvent, atherapeutic agent, and an additive; (2) loading a metering dispenserwith the coating solution; (3) inflating the balloon catheter to 0 to 3atm, and rotating the balloon catheter about the longitudinal axis ofthe catheter and/or moving the balloon catheter in a linear directionalong the longitudinal or transverse axis of the catheter; (4)dispensing the coating solution from the metering dispenser onto asurface of the balloon catheter and flowing the coating solution on thesurface of the balloon catheter while the balloon catheter is rotatingand/or linearly moving; (5) evaporating the solvent, forming a coatinglayer on the surface of the balloon catheter; (6) folding and wrappingthe balloon catheter; and (7) drying and then sterilizing the ballooncatheter. In one embodiment, step (6) comprises deflating, folding,wrapping, and packaging the balloon catheter, and step (7) comprisessterilizing the packaged balloon catheter.

In one embodiment, steps (2), (3), (4), and (5) occur concomitantly.

In one embodiment, the medical device or a portion thereof has acontinuous surface.

In one embodiment, the method for preparing a coated balloon cathetercomprises (1) preparing a coating solution comprising a solvent, atherapeutic agent, and an additive; (2) loading a metering dispenserwith the coating solution; (3) inflating the balloon catheter to 0 to 3atm, and rotating the balloon catheter about the longitudinal axis ofthe catheter and/or moving the balloon catheter in a linear directionalong the longitudinal or transverse axis of the catheter; (4)dispensing the coating solution from the metering dispenser onto asurface of the balloon catheter and flowing the coating solution on thesurface of the balloon catheter while the balloon catheter is rotatingand/or linearly moving; (5) evaporating the solvent, forming a coatinglayer on the balloon catheter; (6) drying, folding and wrapping theballoon catheter; and (7) sterilizing the balloon catheter. In oneembodiment, the method further comprises a step (8) drying the medicaldevice after sterilization. In one embodiment, in step (7) the ballooncatheter is sterilized with ethylene oxide, and in step (8), the ballooncatheter is dried under vacuum at about 0 to 100° C. for approximately 2to 56 hours. In one embodiment, the balloon catheter is dried undervacuum at about 5 to 45° C.

In another embodiment, the method can be used to apply multiple-layercoatings on the surface of a medical device, wherein the methodcomprises (1) preparing a first coating solution comprising a solvent, atherapeutic agent, and an additive; (2) loading a metering dispenserwith the first coating solution; (3) rotating the medical device aboutthe longitudinal axis of the device and/or moving the medical device ina linear direction along the longitudinal or transverse axis of thedevice; (4) dispensing the first coating solution from the meteringdispenser onto a surface of the medical device and flowing the coatingsolution on the surface of the medical device while the medical deviceis rotating and/or linearly moving; (5) evaporating the solvent, forminga substantially uniform coating layer on the surface of the medicaldevice; and (6) repeating steps (1), (2), (3), (4) and (5) with a secondcoating solution, which is the same or different from the first coatingsolution, forming an additional coating layer on the medical device,until the desired number of layers are obtained. In one embodiment, themethod further comprises (7) sterilizing the medical device and (8)drying the medical device after sterilization. In one embodiment, instep (7) the medical device is sterilized with ethylene oxide and instep (8), the medical device is dried under vacuum at about 0 to 100° C.for approximately 2 to 56 hours. In another embodiment, in step (8), themedical device is dried under vacuum at about 5 to 60° C. forapproximately 1 to 120 hours.

In one embodiment, the medical device or a portion thereof has acontinuous surface.

In another embodiment, the method for preparing a medical devicecomprises (1) preparing a coating solution comprising a solvent, atherapeutic agent, and an additive; (2) applying the coating solution toa medical device; (3) drying the coating solution, forming a coatinglayer; (4) sterilizing the medical device; and (5) drying the medicaldevice after sterilization. In one embodiment, the medical device is aballoon catheter and the balloon is inflated under low pressure (0 to 3ATM) during the drug loading and coating. In one embodiment, in step(5), the medical device is dried under vacuum at about 5 to 60° C. forapproximately 1 to 120 hours. In another embodiment, in step (5), themedical device is dried under vacuum at about 0 to 100° C. forapproximately 2 to 56 hours.

In one embodiment, the present invention relates to an apparatus forcoating medical devices, the apparatus comprising a metering dispenser,a coating solution storage container, and an assembly for rotation ofthe device around its central/axial/longitudinal axis and fortranslational movement of the device in a linear direction back andforth along its longitudinal and/or transverse axes. In one embodiment,the assembly moves the device linearly back and forth along a rail withuniform frequency while rotating the device at uniformrotational/tangential speed. In one embodiment, the metering dispensermoves linearly back and forth along a rail with uniform frequency whileas assembly is rotating the device at uniform rotational/tangentialspeed.

In another embodiment of the present invention, an apparatus for coatinga medical device comprises: a metering dispenser; an apparatus thatrotates the medical device around its longitudinal axis and moves themedical device back and forth in the direction of its longitudinal ortransverse axis; a controller coordinating the dispenser and theapparatus; and a coating solution storage container. In one embodiment,the apparatus concurrently rotates the medical device around itslongitudinal axis at uniform rotational or tangential speed andtranslocates the device back and forth at uniform frequency in alongitudinal direction. This enables evaporation of the solvent to occurwhile the coating solution is moving at uniform speed over the surfaceof the medical device, resulting in a uniform dry coating layer.

In another embodiment, the metering dispenser includes a dispensing tip.The dispensing tip typically includes a hub and a tip. The hub isconnected to the metering dispenser. The tip is used to apply coating onthe medical device either by contact or non-contact. The tip opening canhave different shapes including, but not limited to, circular, oval,square, and rectangular. The tip can be straight or with an angle (135°,45° or 90°) and the tip can be rigid or flexible. The tip can betapered, non-tapered, Teflon-lined, Teflon-coated, and Teflon-lined andcrimped or the tip can be a brush. The dispensing tip can be made ofmetals, metal alloys, and a metal with a polymer coating or lining. Forexample, the dispensing tip can be made of stainless steel,polyethylene, polypropylene, polyesters, polyamides, polyurethanes,PTFE, metal with a PTFE coating or lining.

In another embodiment, the dispensing tip has an opening and a flexibletail as illustrated in FIG. 3A. The flexible tip can be metal or polymermaterials. The cross section of the tip can be circular, oval, square,or rectangular. The length of the tip can be from 5 mm to 30 mm. Theflexible tail can thread through the tip opening of the dispensing tipor attach to the side of the tip. In embodiments of the invention, theflexible tail contacts the balloon to be coated. During dispensing, thecoating flows continuously to the balloon surface without formingdroplets. The rotational and traversal movements allow the flexible tailto break the surface tension between the coating and balloon and form auniform coating on the balloon surface.

In some embodiments, the metering dispenser comprises one of a syringe,a syringe pump, a metering pipette, and an automatic metering system. Inone embodiment, the automatic metering system comprises a micro linearpump module, a dispensing controller module, a dispensing tip and otheraccessories from IVEK Corporation. In some embodiments, the devicecomprises one of a balloon catheter, a perfusion balloon catheter, aninfusion catheter such as a distal perforated drug infusion tube, aperforated balloon, a spaced double balloon, a porous balloon, and aweeping balloon, a cutting balloon catheter, a scoring balloon catheter,a laser catheter, an atherectomy device, a debulking catheter, a stent,a filter, a stent graft, a covered stent, a patch, a wire, and a valve.In one embodiment, the method and apparatus of the invention is usefulfor coating the surface of medical devices that have a continuoussurface, for example, the inflatable portion of a balloon catheter,since applying the coating composition on the surface of the medicaldevices while the solvent is evaporating is involved. In one embodiment,the drops of coating solution move back and forth longitudinally andtransversely over the surface of the medical device while the solventevaporates, resulting in the consistent and uniform deposition ofcoating solution over the device surface and resulting in a uniform drycoating layer over the surface of the medical device.

Medical devices with a continuous surface include, among others, aballoon catheter, a perfusion balloon catheter, an infusion cathetersuch as a distal perforated drug infusion tube, a perforated balloon, aporous balloon, and a weeping balloon, a cutting balloon catheter, ascoring balloon catheter, a stent graft, a covered stent, a patch, awire, and leads for pacing, sensing, and defibrillation.

In one embodiment, the coating composition comprises a therapeutic agentand an additive, wherein the additive is at least one of a surfactant, apolymer, and a chemical compound (MW<1300). In embodiments of theinvention, the chemical compound has one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups. In some embodiments,the chemical compound is chosen from amino alcohols, hydroxyl carboxylicacid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxylester, sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, aminoacids, peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. Inembodiments of the invention, the surfactant is chosen from ionic,nonionic, aliphatic, and aromatic surfactants, PEG fatty esters, PEGomega-3 fatty esters, ether, and alcohols, glycerol fatty esters,sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitan fattyesters, sugar fatty esters, PEG sugar esters and derivatives thereof.

In embodiments of the invention, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerols, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, and derivatives and combinations thereof.

In embodiments of the invention, the polymer is one of polyolefins,polyisobutylene, ethylene-α-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, Nylon 12 andits block copolymers, polycaprolactone, polyoxymethylenes, polyesters,polyethers, polyamides, epoxy resins, polyurethanes, rayon-triacetate,cellulose, cellulose acetate, cellulose butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, carboxymethylcellulose, chitins, polylactic acid, polyglycolic acid, polylacticacid-polyethylene oxide copolymers, polyethylene glycol, polypropyleneglycol, polyvinyl alcohol, and mixtures and block copolymers thereof.

In embodiments of the invention, the therapeutic agent is one ofpaclitaxel and analogues thereof, rapamycin and analogues thereof,beta-lapachone and analogues thereof, biological vitamin D and analoguesthereof, and a mixture of these therapeutic agents. In anotherembodiment, the therapeutic agent is in combination with a secondtherapeutic agent, wherein the therapeutic agent is one of paclitaxel,rapamycin, and analogues thereof, and wherein the second therapeuticagent is one of beta-lapachone, biological active vitamin D, and theiranalogues.

In embodiments of the invention, the solvent is one of water, methanol,ethanol, isopropanol, acetone, dimethylformide, tetrahydrofuran,methylethyl ketone, dimethylsulfoxide, acetonitrile, ethyl acetate, andchloroform and mixtures of these solvents.

In one embodiment, the concentration of the therapeutic agent in thecoating layer is from about 1 to about 20 μg/mm². In one embodiment, thethickness of the coating is from about 1 to about 50 μm. In anotherembodiment, the thickness of the coating layer is from about 6 to about20 μm, for example from about 8 to about 15 μm.

In one embodiment comprising a balloon catheter, the balloon diameter isin the range of about 1.0 mm to about 40 mm. In another embodiment ofthe PTCA balloon catheters, the balloon diameter is in the range of fromabout 1.0 mm to about 5.0 mm in 0.25 mm increments. In anotherembodiment of PTA balloon catheters, the balloon diameter is in therange of from about 2.0 mm to about 12.0 mm. In one embodiment ofnon-vascular balloon catheters, the balloon diameter is in the range offrom about 2.0 mm to about 40 mm.

In one embodiment of balloon catheters, the balloon length is in therange of from about 5.0 mm to about 300 mm. In another embodiment of thePTCA balloon catheters, the balloon length is in the range of from about8.0 mm to about 40.0 mm. In another embodiment of PTA balloon catheters,the balloon length is in the range of from about 8.0 mm to about 300.0mm. In one embodiment of non-vascular balloon catheters (for example,gastric and respiratory applications), the balloon length is in therange of from about 10.0 mm to about 200 mm. In one embodiment, theballoon catheter includes a 0.014-inch, 0.018-inch, and 0.035-inch wirecompatible lumen.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of an apparatusaccording to embodiments of the present invention.

FIG. 2 is a perspective view of an exemplary embodiment of an apparatuswith an automatic dispensing system according to embodiments of thepresent invention.

FIGS. 3A to 3E are perspective views of an exemplary embodiment of adispensing tip according to embodiments of the present invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Embodiments of the present invention relate to methods and apparatusesfor coating medical devices, including balloon catheters and othermedical devices with continuous surfaces. A method according toembodiments of the present invention does not require weighing themedical devices after coating to control the concentration or dose ofthe drug on the surface of the devices. An object of embodiments of thepresent invention is to control the dose of the drug by using apremetering dispenser system. The uniformity of coating of the medicaldevice is improved by applying and flowing the fluid of the coatingcomposition on the surface of the medical device in both longitudinaland transverse directions. The coating solution of the present inventionrefers to the liquid drug coating composition and includes a solution,dispersion, suspension, emulsion or other mixture that is dispensed inthe form of a droplet or droplets or continuous flow that then flows onthe surface of the medical device. In certain embodiments, almost noneof the coating solution is lost as the solution is dispensed onto thesurface of the medical device, and no drug is lost while the solvent isevaporated. In these embodiments, since the coating solution is appliedover the entire surface of the device (or portion thereof being coated)at a uniform speed multiple times as the solvent slowly evaporates, auniform dried coating is deployed and remains on the device after thesolvent is evaporated. Furthermore, in contrast to spraying or dippingcoating methods, the metered drug dose dispensed on the surface issubstantially the same as the dose of the drug on the surface of themedical device. The excellent precision of the methods of embodiments ofthe present invention facilitates easy calibration of pipette or metervolume to adjust for measurement errors during solution preparation.

As shown in FIG. 1, in one embodiment, the apparatus is a semi-manualcoating apparatus. The coating apparatus 1 comprises a meteringdispenser 3, a dispenser tip 4, a medical device 5, and an assembly 6for rotation (around the longitudinal axis of the device) andtranslation in a linear direction (back and forth in direction of thelongitudinal or transverse axis of the device). In FIG. 1, the meteringdispenser is a syringe or a pipette. A dispensing tip is connected tothe metering dispenser for easy coating application. In FIG. 1, themedical device is a balloon catheter (only the distal end of the ballooncatheter is shown). Typically, only the inflatable surface of theballoon is coated. The balloon catheter may be any suitable catheter forthe desired use, including conventional balloon catheters known to oneof ordinary skill in the art. The balloon catheter may be a rapidexchange or over-the-wire catheter. The balloon catheter 5 is fixed onthe assembly 6 which rotates the balloon catheter and moves it back andforth linearly in the longitudinal and/or transverse directions.

As shown in FIG. 2, in another embodiment, the apparatus is an automatedcoating apparatus. The coating apparatus 1 comprises a coating solutionstorage container 2, a filter 8, a metering dispenser 3, a dispenser tip4, a fan 9 for accelerating solvent evaporation, a controller 7, forexample a computer, a medical device 5, and an assembly 6 for rotationand translation in a linear direction. In FIG. 2, the metering dispenseris a ceramic micro linear pump (such as micro linear pump module fromIVEK Corporation). The controller is a computer or a digital controller(such as Digispense 2000 controller module, a single channel dispensingsystems from IVEK Corporation). The medical device is a balloon catheterin FIG. 2 (only the distal end of the balloon catheter is shown). Theballoon catheter may be any suitable catheter for the desired use,including conventional balloon catheters known to one of ordinary skillin the art. The balloon catheter may be a rapid exchange orover-the-wire catheter. The storage container 2 is connected to themetering dispenser 3 via a filter 8. The balloon catheter 5 is fixed onthe assembly 6 which rotates the balloon around its longitudinal axisand translocates the balloon catheter 6 linearly in longitudinal andtransverse directions.

As shown in FIG. 3A, in one embodiment the metering dispenser 1 isconnected to a dispensing tip 2. The dispensing tip 2 typically includesa hub 3 and a tip 4. The hub 3 is connected to the metering dispenser.The tip is used to apply coating on the medical device either by contactor non-contact. The tip opening can have different shapes including, butnot limited to, circular, oval, square, and rectangular. The tip can bestraight or with an angle (e.g., 135°, 45° or 90°) and the tip can berigid or flexible. In one embodiment, the dispensing tip has a hub 3, atip 4, and a flexible tail 5. The flexible tail 5 can thread through thetip of the dispensing tip or attach to the side of the tip as shown inFIGS. 3A, 3B, 3C, and 3D.

The coating solution or composition, according to embodiments, isprepared by mixing a fixed amount of a therapeutic agent, an additiveand a solvent. The mixture is then stirred at room temperature or slightheating less than 60° C. until a homogenous solution is obtained. Thesolution is then filtered through a 0.45 micron filter. The meteringdispenser (such as a syringe or a pipette) is used to apply a premeteredcoating solution in the form of droplets onto the surface of ballooncatheter while the balloon catheter is rotating on its longitudinal(axial) axis and moving back and forth linearly in a longitudinal ortransverse direction. The coating uniformity is obtained by applying acontinuous flow or droplets of a coating solution or composition andflowing the solution or composition onto the surface of the balloonwhile the solvent is evaporating. The balloon is folded after thecoating is solidified. The dried and folded balloon catheter is thenrewrapped. The right sized balloon protector is then put on the wrappedballoon. The balloon catheter is packaged. The balloon catheter is thensterilized with ethylene oxide, E-beam or other methods. The ballooncatheter is then ready for animal testing or human trials or fortreating diseases such as coronary or peripheral artery stenosis.

In some embodiments, the coating properties of the coating layer arefurther improved by drying after sterilization either with or withoutvacuum for a period of time (for example approximately 2 to 56 hours) ata selected temperature (such as at or above room temperature or below50° C.) in order to remove the moisture in the coating.

The drying process improves integrity of the coating layer, protectsloss of coating components during transit through body passages to thetarget treatment site, and improves drug absorption in the tissue. Themoisture in the coating changes the balance of the hydrophilic andhydrophobic components in the coating. The moisture in the coating alsoaccelerates release of the drug and additive in vivo and in vitro fromthe surface of the device. The moisture reduces drug retention duringthe delivery of the balloon catheter to the target site and acceleratesdrug loss during the initial phase of inflation of the balloon (or otherinflatable component of the medical device). The loss of drug during thedelivery and inflation decreases the amount of drug that remains and isavailable to be delivered at the target site. This can result in lessthan optimal, highly variable, and even less than therapeutic drugconcentration levels in the tissue after deployment.

A drying step after sterilization removes moisture, decreases drug lossduring transit, and increases drug levels in tissue after deployment.Perhaps equally important, by decreasing drug loss during transit, thedrying step after sterilization decreases a major source of variabilityin tissue concentration levels of drug and thereby improves consistencyof the therapeutic effect of the medical device. The removal of moistureis even more important when a large percentage of coating components arehydrophilic. A drying step after sterilization, optionally under vacuumand at a specific temperature between room temperature and 50° C.,optimizes coating properties such that optimal and consistenttherapeutic levels of drug are delivered to the tissue by the medicaldevice.

Preparation

The medical device and the coating solution of embodiments of thepresent invention can be made according to various methods. For example,the coating solution can be prepared by dispersing, dissolving,diffusing, or otherwise mixing all the ingredients, such as atherapeutic agent, an additive, and a solvent, simultaneously together.Alternatively, the coating solution can be prepared by sequentiallyadding each component based on solubility or any other parameters. Forexample, the coating solution can be prepared by first adding thetherapeutic agent to the solvent and then adding the additive.Alternatively, the additive can be added to the solvent first and thenthe therapeutic agent can be later added. If the solvent used does notsufficiently dissolve the drug, it is preferable to first add theadditive to the solvent, then the drug, since the additive will increasedrug solubility in the solvent. Alternatively, combinations of two ormore solvents are used, for example, by combining two solvents prior toaddition of drug and additive, or by adding drug to one solvent andadditive to another solvent and then combining, or by adding only one ofdrug or additive to one solvent and then adding the second solvent andfinally the other drug or additive.

In some cases, for example in the case of a protective top layer that isto be coated over a drug layer already deployed on the device (bymethods of the present invention or by others), a drug may not beincluded in the coating solution, and the coating solution mayessentially consist of solvent and additive.

Therapeutic Agent

The drugs or biologically active materials, which can be used inembodiments of the present invention, can be any therapeutic agent orsubstance. The drugs can be of various physical states, e.g., moleculardistribution, crystal forms or cluster forms. Examples of drugs that areespecially useful in embodiments of the present invention arelipophilic, substantially water insoluble drugs, such as paclitaxel,rapamycin, daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 andanalogues and derivatives thereof. These drugs are especially suitablefor use in a coating on a balloon catheter used to treat tissue of thevasculature.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, anti-proliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, and anti-inflammatory agents.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents for use in embodiments of the present invention caninclude drugs such as aspirin and dipyridamole. Aspirin is classified asan analgesic, antipyretic, anti-inflammatory and anti-platelet drug.Dipyridamole is a drug similar to aspirin in that it has anti-plateletcharacteristics. Dipyridamole is also classified as a coronaryvasodilator. Anti-coagulant agents for use in embodiments of the presentinvention can include drugs such as heparin, protamine, hirudin and tickanticoagulant protein. Anti-oxidant agents for use in embodiments of thepresent invention can include probucol. Anti-proliferative agents foruse in embodiments of the present invention can include drugs such asamlodipine and doxazosin. Anti-mitotic agents and anti-metabolite agentsthat can be used in embodiments of the present invention include drugssuch as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluoroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, coichicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, .beta.-sitosterin, ademetionine, myrtecaine, polidocanol,nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferona, .beta and y, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or Bcl-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamide, retinoic acid, quinidine, disopyramide,flecamide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside 1a, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Additive

In certain embodiments of the present invention, the additive has twoparts. One part is hydrophilic and the other part is a drug affinitypart. The drug affinity part is a hydrophobic part and/or has anaffinity to the therapeutic agent by hydrogen bonding and/or van derWaals interactions. The drug affinity part of the additive may bind thelipophilic drug, such as rapamycin or paclitaxel. The hydrophilicportion accelerates diffusion and increases permeation of the drug intotissue. The drug affinity part may include aliphatic and aromaticorganic hydrocarbon groups, such as benzene, toluene, and alkanes, amongothers. These parts are not water soluble. They may bind bothhydrophobic drug, with which they share structural similarities, andlipids of cell membranes. The hydrophilic part may include hydroxylgroups, amine groups, amide groups, carbonyl groups, carboxylic acid andanhydrides, ethyl oxide, ethyl glycol, polyethylene glycol, ascorbicacid, amino acid, amino alcohol, glucose, sucrose, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic salts and their substitutedmolecules, among others.

The additive in embodiments of the present invention is at least one ofa surfactant, a polymer, and a chemical compound (MW<1300). In oneembodiment, the chemical compound has one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups. In embodiments of theinvention, the chemical compound is chosen from amino alcohols, hydroxylcarboxylic acid, ester, anhydrides, hydroxyl ketone, hydroxyl lactone,hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide, ethylglycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohol and organic acid, and theirsubstituted molecules. In embodiments of the invention, the surfactantis chosen from ionic, nonionic, aliphatic, and aromatic surfactants, PEGfatty esters, PEG omega-3 fatty esters, ether, and alcohols, glycerolfatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEGsorbitan fatty esters, sugar fatty esters, PEG sugar esters andderivatives thereof.

In embodiments of the invention, the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, Tween 20, Tween 40, Tween 60, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerols, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, and derivatives and combinations thereof.

In embodiments of the invention, the polymer is one of polyolefins,polyisobutylene, ethylene-α-olefin copolymers, acrylic polymers andcopolymers, polyvinyl chloride, polyvinyl methyl ether, polyvinylidenefluoride and polyvinylidene chloride, polyacrylonitrile, polyvinylketones, polystyrene, polyvinyl acetate, ethylene-methyl methacrylatecopolymers, acrylonitrile-styrene copolymers, ABS resins, Nylon 12 andits block copolymers, polycaprolactone, polyoxymethylenes, polyesters,polyethers, polyamides, epoxy resins, polyurethanes, rayon-triacetate,cellulose, cellulose acetate, cellulose butyrate, cellophane, cellulosenitrate, cellulose propionate, cellulose ethers, carboxymethylcellulose, chitins, polylactic acid, polyglycolic acid, polyethyleneoxide, polylactic acid-polyethylene oxide copolymers, polyethyleneglycol, polypropylene glycol, polyvinyl alcohol, polyvinylpyrrolidone,and mixtures and block copolymers thereof.

Solvents

In embodiments of the invention, solvents for preparing of the coatinglayer may include, as examples, any combination of one or more of thefollowing: (a) water, (b) alkanes such as hexane, octane, cyclohexane,and heptane, (c) aromatic solvents such as benzene, toluene, and xylene,(d) alcohols such as methonal, ethanol, propanol, and isopropanol,diethylamide, ethylene glycol monoethyl ether, Trascutol, and benzylalcohol (e) ethers such as dioxane, dimethyl ether and tetrahydrofuran,(f) esters/acetates such as ethyl acetate and isobutyl acetate, (g)ketones such as acetone, acetonitrile, diethyl ketone, and methyl ethylketone, and (h) mixture of water and organic solvents such aswater/ethanol, water/acetone, water/methanol, water/ethanol/acetone,water/tetrahydrofuran.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful and preferred solvents in embodiments ofthe present invention because these organic solvents generally disruptcollodial aggregates and co-solubilize all the components in the coatingsolution.

The therapeutic agent and additive or additives may be dispersed in,solubilized, or otherwise mixed in the solvent. The weight percent ofdrug and additives in the solvent may be in the range of 0.1 to 80% byweight, preferably 2 to 20% by weight.

Another embodiment of the invention relates to a method for preparing amedical device, particularly, for example, a balloon catheter or astent. First, a coating solution or suspension comprising, for example,at least one solvent, at least one therapeutic agent, and at least oneadditive is prepared. In at least one embodiment, the coating solutionor suspension includes only these three components. The content of thetherapeutic agent in the coating solution can be from 0.5 to 50% byweight based on the total weight of the solution. The content of theadditive in the coating solution can be from 1 to 45% by weight, 1 to40% by weight, or from 1 to 15% by weight based on the total weight ofthe solution. The amount of solvent used depends on the coating processand viscosity. It will affect the uniformity of the drug-additivecoating but will be evaporated after coating solution is applied.

In other embodiments, two or more solvents, two or more therapeuticagents, and/or two or more additives may be used in the coatingsolution.

Medical Device

Implantable and non-implantable medical devices may be coated using themethods and apparatus of the present invention. Examples of coatedmedical devices include a balloon catheter, a perfusion ballooncatheter, an infusion catheter such as a distal perforated drug infusiontube, a perforated balloon, a spaced double balloon, a porous balloon, aweeping balloon, a cutting balloon catheter, a scoring balloon catheter,a laser catheter, an atherectomy device, a debulking catheter, a stent,a filter, a stent graft, a covered stent, a patch, a wire, a valve,leads or implantable pulse generators, pacers or neurostimulators, amongothers. In one embodiment, the methods and apparatuses of the presentinvention are especially useful for coating continuous surfaces onmedical devices, since continuous flowing of the coating compositionover the surface of the medical devices is involved. Medical deviceswith continuous surfaces include a balloon catheter, a perfusion ballooncatheter, an infusion catheter such as a distal perforated drug infusiontube, a perforated balloon, a porous balloon, and a weeping balloon, acutting balloon catheter, a scoring balloon catheter, a stent graft, acovered stent, a patch, a wire, and leads for pacing, sensing, anddefibrillation.

In one embodiment of balloon catheters, the balloon diameter is in therange of 1.0 mm to 40 mm. In another embodiment of the PTCA ballooncatheters, the balloon diameter is in the range of 1.0 mm to 5.0 mm in0.25 mm increments. In another embodiment of PTA balloon catheters, theballoon diameter is in the range of 2.0 mm to 12.0 mm. In one embodimentof non vascular balloon catheters, the balloon diameter is in the rangeof 2.0 mm to 40 mm.

In one embodiment of balloon catheters, the balloon length is in therange of 5.0 mm to 300 mm. In another embodiment of the PTCA ballooncatheters, the balloon length is in the range of 8.0 mm to 40.0 mm. Inanother embodiment of PTA balloon catheters, the balloon length is inthe range of 8.0 mm to 300.0 mm. In one embodiment of non vascularballoon catheters (for example, gastric and respiratory applications),the balloon length is in the range of 10.0 mm to 200 mm.

Dispensing System

Dispensing systems in embodiments of the invention comprise a coatingsolution container, a metering dispenser, a dispenser tip, and aprogrammable controller. The metering dispenser includes a syringe pump,a micro-metering pump, a dispensing pipette, and an automatic meteringpump system. The metering dispenser is able to dispense from 1 μL to1000 μL. A dispensing tip is connected to the metering dispenser foreasy coating application. The dispensing tip typically includes a huband a tip. The hub is connected to the metering dispenser. The tip isused to apply coating on the medical device either by contact ornon-contact. The tip opening can have different shapes including, butnot limited to, circular, oval, square, and rectangular. The diameter ofthe tip opening ranges from about 10 micron-meters to about 3 mm, forexample from about 50 micro-meters to about 500 micro-meters, or fromabout 0.05 mm to about 2 mm. The length of the dispensing tip rangesfrom about 5 mm to about 70 mm, for example from about 10 mm to about 30mm, or from about 30 mm to about 50 mm. The tip can be straight or withan angle (e.g., 135°, 45° or 90°) and the tip can be rigid or flexible.The tip can be tapered, non-tapered, Teflon-lined, Teflon-coated,Teflon-lined and crimped, or the tip can be a brush. The dispensing tipcan be made of metals, metal alloys, metal with a polymer coating orlining. For example, the dispensing tip can be made of stainless steel,polyethylene, polypropylene, polyesters, polyamides, polyurethanes,PTFE, and/or metal with a PTFE coating or lining.

There are many kinds of pipettes from various manufacturers, such asBrinkman Eppendorf research pipette, Fisherbrand finnpipette pipette,Corning Lambda pipette, Wheaton Socorex Acura micropipetter and HamiltonSoftGrip pipette. One preferable pipette in embodiments of the inventionis the digital single channel air displacement pipette. The adjustablevolume ranges from 0.02 ml to 10 ml. The fast-dial system allows 0.1 μlfine adjustment. The dispensing also can be done with a stepper pipette,such as Finnpipette Stepper pipette from Thermo Electron and BrandHandyStep repeating pipette from BrandTech. The electronicmicropipetters can be used in embodiments of the invention according tothe volume to be used. The pipette tips can be used as the dispensingtips in all of dispensing systems.

The syringe pump can be also used for this application. There are bothsingle channel and multiple channel syringe pumps, for example,Cole-Parmer single-syringe infusion pump features microprocessor motorcontrol and precision gearing. The flow rate can be as low as 0.2 μl/hr.The accuracy can be as low as ±0.5%, and reproducibility can be as lowas ±0.2%. The syringe size can be from 10 μl to 60 ml.

A programmable dispensing system may use precision stepper motors tocontrol ceramic piston pumps. This type of programmable dispensingsystem can dispense from 500 nanoliters per dispense to 0.5 liters perminute continuous flow. It has single and dual channel flowconfiguration. One example of a programmable dispensing system is aSensata programmable dispensing system from Fluid metering, Inc. Anotherexample is the automatic metering system from IVEK Corporation. Itincludes a dispensing controller module, micro linear, pump module andother accessories. The controller modules single channel,microprocessor-based units contain all the control, monitoring, andinterface components. The controller provides very accurate and precisefluid dispensing and metering. The micro linear pump module is comprisedof a ceramic piston fabrication and mated ceramic cylinder installedinto a case with intake and discharge ports. The micro linear pump sizesinclude several models, for an example, 20 μl chamber, 0.010 μlresolution, 50 μl chamber, 0.025 μl resolution, 100 μl chamber, 0.050 μlresolution, and 200 μl chamber, 0.100 μl resolution.

Rotation and Transverse Movement Assembly

The rotation and transverse movement assembly is to provide linear androtation movement during the solution dispensing and after solutiondispensing. During dispensing, the device to be coated, dispensing tipor both can move transversely or rotationally. After dispensing, onlythe device to be coated moves transversely and rotationally. The linearspeed, distance and rotation speed are controlled to achieve the bestcoating quality. The rotation speed is in the range of 0.1 to 10revolutions per second, preferably from 0.5 to 5 revolutions per second,most preferably from 0.8 to 2 revolutions per second. The linear ortransverse speed is the range of from 0.1 to 100 mm per second,preferably from 1 to 75 mm per second, most preferably from 2 to 50 mmper second. The dispensing time is in the range of from 2 to 300seconds, preferably from 5 to 120 seconds, which depends on thedispensing coating volume and diameters (1.5 mm to 12 mm) and lengths (5to 200 mm) of the balloon catheters. After the dispensing of the coatingsolution on the balloon, the coating solution flows and solidifies onthe surface of the balloon during the transverse and rotational motionof the device to be coated. The flowing of the coating leads to a moreuniform coating on the surface of the device. The time of flowing andsolidification of the coating on the balloon after dispensing of theliquid coating is in the range of from 0.1 to 10 minutes, preferablyfrom 0.5 to 5 minutes. The coated balloon catheters are then dried atroom temperature for 12 to 24 hours. The balloon catheters are thenfolded, rewrapped, packaged, and sterilized under ethylene oxide.

EXAMPLES

The following examples include embodiments of medical devices andcoating layers within the scope of the present invention. While thefollowing examples are considered to embody the present invention, theexamples should not be interpreted as limitations upon the presentinvention.

Example 1

Preparation of coating solutions: 70 mg of Octanoyl-N-methylglucamidewas added into 1.0 ml of solvent mixture (50% acetone and 50% ethanol).Then, 35 mg of paclitaxel was added into the solution. The solution wasmixed at room temperature until a homogeneous solution was obtained.

A PTCA balloon catheter (3.5 mm in diameter and 20 mm in length) wasinflated at 2 atm. A pipette (Fisher Scientific, Finnpipette 5-50 μl)was used to pipette 25 μl of solution, and then the solution wastransferred onto the inflated 3.5 mm×20 mm balloon catheter. Thesolution was flowing on the surface of the balloon while the balloon wasmoving both circumferentially and longitudinally. The time of flowingand evaporation of the solvent and solidification of the coating isabout 1 minute after the dispensing of the coating solution on thesurface of the balloon catheter. The residual solvent was evaporated andthe coating was dried at room temperature for 12 hours. The balloon wasfolded, rewrapped and packaged, then sterilized with ethylene oxide. Thedrug loading was 3.75 μg/mm² from HPLC analysis.

The coated PTCA balloon catheter was inserted into a target site in thecoronary vasculature (LAD, LCX and RCA) of a 25 to 45 kg pig. Theballoon was inflated to approximately 12 atm. The overstretch ratio (theratio of balloon diameter to vessel diameter) was about 1.15 to 1.20.The drug was delivered into the target tissue during 30 to 60 seconds ofinflation. The balloon catheter was then deflated and was withdrawn fromanimal body. The target blood vessel was harvested 0.25 to 24 hoursafter the procedure. The drug content in the target tissue and theresidual drug remaining on the balloon were analyzed by tissueextraction and HPLC.

In chronic animal tests, angiography was performed before and after allinterventions and at 28 days after the procedure. In some cases, a stentwas first crimped on the coated balloon catheter and deployed by thecoated catheter into a target site of the coronary vasculature. Luminaldiameters were measured and late lumen loss was calculated. Late lumenloss is the difference between the minimal lumen diameter measured aftera period of follow-up time (usually weeks to months after anintervention, such as angioplasty and stent placement in the case ofthis example) and the minimal lumen diameter measured immediately afterthe intervention. Restenosis is quantified by the diameter stenosis,which is the difference between the mean lumen diameters at follow-upand immediately after the procedure divided by the mean lumen diameterimmediately after the procedure. The animal test results are reportedbelow. All data is an average of five or six experimental data points.

After the procedure, the residual drug on the balloon was 13.7 μg. Thedrug content in tissue harvested 60 minutes after the procedure was 45.2μg. When the drug coated balloon was used to deploy a pre-crimped baremetal stent, the late lumen loss after 28 days was 0.49 mm (STDEV 0.26mm). The diameter stenosis was 11.3%.

Example 2

Preparation of coating solutions: 35 mg of Octanoyl-N-methylglucamideand 35 mg of Tween 20 were added into 1.0 ml of solvent mixture (50%acetone and 50% ethanol). Then, 35 mg of paclitaxel was added into thesolution. The solution was mixed at room temperature until a homogeneoussolution was obtained.

A PTCA balloon catheter (3.5 mm in diameter and 20 mm in length) wasinflated at 2 atm. A pipette (Fisher Scientific, Finnpipette 5-50 μl)was used to pipette 23 μl of solution (volume calibrated for dispensingof 660 μg drug), and then the solution was transferred onto the inflated3.5 mm×20 mm balloon catheter and the solution was flowing on thesurface of the balloon while the balloon was moving bothcircumferentially and longitudinally. The time of flowing and solventevaporation and solidification of the coating is about 1 minute afterthe dispensing of the coating solution on the surface of the ballooncatheter. The residual solvents were evaporated and the coating wasdried at room temperature for 12 hours. The balloon was folded,rewrapped and packaged, then sterilized with ethylene oxide. The drugloading was 3.08 μg/mm² from HPLC analysis.

The animal tests and measurements are the same as in the Example 1.After the procedure, the residual drug on the balloon was 21.3 μg. Thedrug content in tissue harvested 60 minutes after the procedure was 42.2μg. The late lumen loss after 28 days was 0.3 mm (STDEV 0.23 mm). Thediameter stenosis is 5.4%.

Example 3

Preparation of base layer coating solutions: 35 mg of lactobionic acidand 10 mg of diethanolamine were added into 1.0 ml of solvent mixture(25% water, 37.5% acetone and 37.5% ethanol). Then, 35 mg of paclitaxelwas added into the solution. The solution was mixed at room temperatureor at 50° C. until a homogeneous solution was obtained.

Preparation of top layer coating solutions: 35 mg of methylparaben wasadded into 1.0 ml of acetone. The solution was mixed at room temperatureuntil a homogeneous solution was obtained.

A PTCA balloon catheter (3.5 mm in diameter and 20 mm in length) wasinflated at 2 atm. A pipetter (Fisher Scientific, Finnpipette 5 to 50μl) was used to pipette 25 μl of solution (volume calibrated fordispensing of 770 μg drug), and then the solution was transferred ontothe inflated 3.5 mm×20 mm balloon catheter and the solution was flowingon the surface of the balloon while the balloon was moving bothcircumferentially and longitudinally. The solvents were evaporated andthe coating was dried at room temperature for 12 hours. After the baselayer coating was dried, the catheter was inflated again at 1.5 to 3atm. A pipette (Fisher Scientific, Finnpipette 5 to 50 μl) was used topipette 25.0 μl of top layer coating solution, and then the solution wastransferred onto the 3.5 mm×20 mm balloon catheter while the balloon wasmoving both circumferentially and longitudinally. The time of flowingand solvent evaporation and solidification of the coating is about 1minute after the dispensing of the coating solution on the surface ofthe balloon catheter. The residual solvent was evaporated and thecoating was dried at room temperature for 12 hours. After the top layercoating was dried, the balloon was folded, rewrapped and packaged, thensterilized with ethylene oxide. The drug loading was 3.68 μg/mm² fromHPLC analysis.

The animal tests and measurements are the same as in the Example 1.After the procedure, the residual drug on the balloon was 44.4 μg. Thedrug content in tissue harvested 15 minutes after the procedure was22.96 μg.

Example 4

Preparation of coating solutions: 70 mg of Octanoyl-N-methylglucamidewas added into 1.0 ml of solvent mixture (50% acetone and 50% ethanol).Then, 35 mg of paclitaxel was added into the solution. The solution wasmixed at room temperature until a homogeneous solution was obtained.

A balloon catheter (6.0 mm in diameter and 40 mm in length) was inflatedat 2 atm. A pipetter (Fisher Scientific, Finnpipette 10 to 100 μl) wasused to pipette 90 μl of solution, and then the solution was transferredonto the inflated 6.0 mm×40 mm balloon catheter and the solution wasflowing on the surface of the balloon while the balloon was moving bothcircumferentially and longitudinally. The time of flowing and solventevaporation and solidification of the coating is about 1 minute afterthe dispensing of the coating solution on the surface of the ballooncatheter. The coating was dried at room temperature for 12 hours. Theballoon was folded, rewrapped and packaged, then sterilized withethylene oxide.

Example 5

Preparation of coating solutions: 35 mg of gluconolactone was added into1.0 ml of solvent mixture (20% water, 40% acetone and 40% ethanol).Then, 35 mg of paclitaxel was added into the solution. The solution wasmixed at room temperature or at 50° C. until a homogeneous solution wasobtained.

Twenty-four PTCA balloon components (3.5 mm in diameter and 20 mm inlength) were used for the repeatability test. Each balloon was coatedwith a pipette (Fisher Scientific, Finnpipette 5 to 50 μl) bytransferring 22 μl of solution (volume calibrated for 660 μg drug) ontothe balloon and the solution was flowing on the surface of the balloonwhile the balloon was moving both circumferentially and longitudinally.The time of flowing and evaporation of solvent and solidification of thecoating is about 1 minute after the dispensing of the coating solutionon the surface of the balloon catheter. Residual solvents wereevaporated and the coating was dried at room temperature for 12 hours.The drug loading of each balloon was analyzed by HPLC. The average drugloading was 644.78 μg and the relative standard deviation was 5.2%. Theexcellent precision allows for easy calibration of pipette or metervolume to adjust for measurement errors during solution preparation.

Example 6

Preparation of coating solutions: 10 mg of gluconolactone was added into1.0 ml of solvent mixture (20% water, 40% acetone and 40% ethanol).Then, 15.5 mg of paclitaxel was added into the solution. The solutionwas mixed at room temperature until a homogeneous solution was obtained.

Ten PTCA balloon catheters (3.0 mm in diameter and 20 mm in length) wereused for the repeatability test. Each balloon catheter was inflated andcoated with a pipette (Fisher Scientific, Finnpipette 5 to 50 μl) bytransferring 21.5 μl of solution onto the balloon. The solution wasflowing on the surface of the balloon while the balloon was moving bothcircumferentially and longitudinally. The time of flowing and solventevaporation and solidification of the coating is about 1 minute afterthe dispensing of the coating solution on the surface of the ballooncatheter. The residual solvents were evaporated and the coating wasdried at room temperature for 12 hours. After the first layer coatingwas dried, the catheter was inflated again at 1.5 to 3 atm. A pipette(Fisher Scientific, Finnpipette 5 to 50 μl) was used to pipette 21.5 μlof coating solution, and then the solution was transferred onto the 3.0mm×20 mm balloon catheter while the balloon was moving bothcircumferentially and longitudinally. The solvent was evaporated and thecoating was dried at room temperature for 12 hours. After the secondlayer coating was dried, the balloon was folded, rewrapped and packaged,then sterilized with ethylene oxide. The drug loading on each catheterwas analyzed by HPLC. The average drug loading was 648.52 μg and therelative standard deviation was 5.1%. The expected drug load from twoapplications of 21.5 μl solution containing 15.5 mg/ml paclitaxel is666.5 μg, demonstrating accuracy of greater than 97% for the coatingmethod.

Similar results are expected when the coating formulation is applied tothe balloon surface using a rotating and transverse movement apparatusin accordance with embodiments of the present invention.

Example 7

Twelve PTCA balloon catheters (3.0 mm in diameter and 20 mm in length)were loaded with the coating solution of Example 1 (creating a firstcoating layer). The desired amount of drug (3 μg/mm²) was obtained onthe balloon surface.

A formulation for a top coating layer was then prepared. The formulationof the top coating layer was Tween 20 in acetone. 0.7 mg of the topcoating formulation was coated over the first coating layer on twelveballoon surfaces. The coated balloons were dried. The catheters weresterilized under standard ethylene oxide sterilization. Aftersterilization, six of the PTCA balloon catheters were dried under vacuumat 45° C. for 24 hours. The other six PTCA balloon catheters, whichserved as the control, were not dried. The results showed that theadhesion of the coating on the surface of the balloon is improved withvacuum dry after sterilization. In addition, retention of the coating isimproved in experiments in which the coated balloon is floated in aporcine aorta, and the drug absorption into vessel wall tissue isimproved as well.

Example 8

Three hundred PTCA balloon catheters (2.5 mm in diameter and 18 mm inlength) were used for the test. Each balloon catheter was inflated andcoated with a semi-automatic coater by dispensing 16 μl of solution(volume calibrated for dispensing 300 μg target drug) onto the balloon.The solution flowed on the surface of the balloon while the balloon wasmoving both circumferentially and longitudinally. The time of flow andsolvent evaporation and solidification of the coating was about 1 minuteafter the dispensing of the coating solution on the surface of theballoon catheter. The residual solvents were evaporated, and the coatingwas dried at room temperature for 12 hours. After the coating was dried,the balloon was folded, rewrapped and packaged, then sterilized withethylene oxide. The catheters were vacuum dried after sterilization.Then, ten catheters were randomly taken from the three-hundred cathetersfor analysis. The drug loading on each catheter was analyzed by HPLC andlisted in the following table.

catheters 1 2 3 4 5 6 7 8 9 10 Drug loading 300.7 280.9 296.3 292.8268.5 284.8 312.0 299.2 298.4 299.6 (μg) The average drug loading was293.3 μg, and relative standard deviation was 4.2%.

The numerical values set forth in the Example are reported as preciselyas possible. The numerical values, however, inherently contain someimprecision necessarily resulting from the standard deviation found intheir respective testing measurements, e.g., sample weighing, solutionpreparation, and sample analysis.

Example 9

Three hundred PTCA balloon catheters (3.0 mm in diameter and 18 mm inlength) were used for the test. Each balloon catheter was inflated andcoated with a semi-automatic coater by dispensing 19 μl of solution(volume calibrated for dispensing 350 μg target drug) onto the balloon.The solution was flowed on the surface of the balloon while the balloonwas moving both circumferentially and longitudinally. The time of flowand solidification of the coating was about 1 minute after thedispensing of the coating solution on the surface of the ballooncatheter. Residual solvents were evaporated, and the coating was driedat room temperature for 12 hours. After the coating was dried, theballoon was folded, rewrapped and packaged, then sterilized withethylene oxide. The catheters were vacuum dried after sterilization.Then, ten catheters were randomly taken from the three-hundred cathetersfor analysis. The drug loading on each catheter was analyzed by HPLC andlisted in the following table.

catheters 1 2 3 4 5 6 7 8 9 10 Drug loading 347.0 369.3 351.4 365.0359.3 362.6 339.3 335.7 352.3 305.7 (μg) The average drug loading was348.8 μg, and relative standard deviation was 5.3%.

The numerical values set forth in the Example are reported as preciselyas possible. The numerical values, however, inherently contain someimprecision necessarily resulting from the standard deviation found intheir respective testing measurements, e.g., sample weighing, solutionpreparation, and sample analysis.

Example 10

Three hundred PTCA balloon catheters (2.5 mm in diameter and 30 mm inlength) were used for the test. Each balloon catheter was inflated andcoated with a semi-automatic coater by dispensing 26 μl of solution(volume calibrated for dispensing 490 μg target drug) onto the balloon.The solution was flowed on the surface of the balloon while the balloonwas moving both circumferentially and longitudinally. The time of flowand solidification of the coating was about 1 minute after thedispensing of the coating solution on the surface of the ballooncatheter. Residual solvents were evaporated, and the coating was driedat room temperature for 12 hours. After the coating was dried, theballoon was folded, rewrapped and packaged, then sterilized withethylene oxide. The catheters were vacuum dried after sterilization.Then, ten catheters were randomly taken from the three-hundred cathetersfor analysis. The drug loading on each catheter was analyzed by HPLC andlisted in the following table.

catheters 1 2 3 4 5 6 7 8 9 10 Drug loading 492.6 474.7 490.0 497.7496.9 507.9 503.0 495.2 488.5 505.0 (μg) The average drug loading was495.2 μg, and relative standard deviation was 1.9%.

The numerical values set forth in the Example are reported as preciselyas possible. The numerical values, however, inherently contain someimprecision necessarily resulting from the standard deviation found intheir respective testing measurements, e.g., sample weighing, solutionpreparation, and sample analysis.

Example 11

Three hundred PTCA balloon catheters (3.0 mm in diameter and 30 mm inlength) were used for the test. Each balloon catheter was inflated andcoated with a semi-automatic coater by dispensing 31 μl of solution(volume calibrated for dispensing of 570 μg target drug) onto theballoon. The solution was flowed on the surface of the balloon while theballoon was moving both circumferentially and longitudinally. The timeof flow and solidification of the coating was about 1 minute after thedispensing of the coating solution on the surface of the ballooncatheter. The solvents were evaporated, and the coating was dried atroom temperature for 12 hours. After the coating was dried, the balloonwas folded, rewrapped and packaged, then sterilized with ethylene oxide.The catheters were vacuum dried after sterilization. Then, ten catheterswere randomly taken from the three-hundred catheters for analysis. Thedrug loading on each catheter was analyzed by HPLC and listed in thefollowing table.

catheters 1 2 3 4 5 6 7 8 9 10 Drug loading 549.5 610.7 596.1 547.7569.7 564.6 594.7 587.2 593.2 599.1 (μg) The average drug loading was581.3 μg, and relative standard deviation was 3.8%.

The numerical values set forth in the Example are reported as preciselyas possible. The numerical values, however, inherently contain someimprecision necessarily resulting from the standard deviation found intheir respective testing measurements, e.g., sample weighing, solutionpreparation, and sample analysis.

Example 12

Five PTCA balloon catheters (2.25 mm in diameter and 40 mm in length)and five PTCA balloon catheters (4.0 mm in diameter and 40 mm in length)were coated using the method described in Example 11. Each ballooncatheter was inflated and coated with a calibrated volume of drugsolution using a semi-automatic coater. The solution was flowed on thesurface of the balloon while the balloon was moving bothcircumferentially and longitudinally. The time of flow andsolidification of the coating is about 1 minute after the dispensing ofthe coating solution on the surface of the balloon catheter. Theresidual solvents were evaporated, and the coating was dried at roomtemperature for 12 hours. Each balloon on the catheter was cut intothree equal sections, and drug on each section was analyzed by HPLC andlisted in the following tables, demonstrating uniformity of the coatingacross segments of the coated balloon catheter.

Balloon (2.25 mm × 40 mm) Number Section Percent of Coating 1 S1 37.2%S2 36.1% S3 26.7% 2 S1 34.4% S2 32.5% S3 33.1% 3 S1 37.4% S2 32.5% S330.2% 4 S1 33.2% S2 36.8% S3 30.0% 5 S1 32.4% S2 36.7% S3 30.9%

Balloon (4.0 mm × 40 mm) Number Section Percent of Coating 1 S1 28.2% S230.4% S3 41.3% 2 S1 34.0% S2 30.0% S3 36.0% 3 S1 27.5% S2 29.9% S3 42.6%4 S1 31.3% S2 31.5% S3 37.2% 5 S1 35.2% S2 29.2% S3 35.6%

1. A method for preparing a substantially uniform coated medical device,comprising: (1) preparing a coating solution comprising a solvent, atherapeutic agent, and an additive; (2) loading a metering dispenserwith the coating solution; (3) rotating the medical device about thelongitudinal axis of the medical device and/or moving the medical devicein a linear direction along the longitudinal or transverse axis of themedical device; (4) dispensing the coating solution from the meteringdispenser onto a surface of the medical device and flowing the coatingsolution on the surface of the medical device while the medical deviceis rotating and/or linearly moving; and (5) evaporating the solvent,forming a substantially uniform coating layer on the medical device. 2.The method according to claim 1, wherein the medical device is chosenfrom a balloon catheter, a perfusion balloon catheter, an infusioncatheter such as a distal perforated drug infusion tube, a perforatedballoon, a spaced double balloon, a porous balloon, a weeping balloon, acutting balloon catheter, a scoring balloon catheter, a laser catheter,an atherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve.
 3. The methodaccording to claim 1, wherein the metering dispenser comprises at leastone of a syringe, a syringe pump, a metering pipette, and an automaticmetering system.
 4. The method according to claim 1, wherein steps (2),(3), (4) and (5) occur concomitantly.
 5. The method according to claim1, wherein steps (2), (3), (4) and (5) are repeated until atherapeutically effective amount of the therapeutic agent in the coatingis deposited on the surface of the medical device.
 6. The methodaccording to claim 1, wherein the total thickness of the coating layeris from about 0.1 to 200 microns.
 7. The method according to claim 1,wherein the concentration of the therapeutic agent in the coating layeris from 1 to 20 μg/mm².
 8. The method according to claim 1, wherein themethod further comprises (6) drying the medical device, (7) sterilizingthe medical device, and (8) drying the medical device aftersterilization.
 9. The method according to claim 8, wherein in step (7)the medical device is sterilized with ethylene oxide, and wherein instep (8) the medical device is dried under vacuum at about 0 to 100° C.for approximately 2 to 56 hours.
 10. A method for preparing asubstantially uniform coated balloon catheter, the method comprising:(1) preparing a coating solution comprising a solvent, a therapeuticagent, and an additive; (2) loading a metering dispenser with thecoating solution; (3) inflating the balloon catheter to a low pressureand rotating the balloon catheter about the longitudinal axis of thecatheter and/or moving the balloon catheter in a linear direction alongthe longitudinal or transverse axis of the catheter; (4) dispensing thecoating solution from the metering dispenser onto a surface of theballoon catheter and flowing the coating solution on the surface of theballoon catheter while the balloon catheter is rotating and/or linearlymoving; (5) evaporating the solvent, forming a substantially uniformcoating layer on the balloon catheter; (6) folding and wrapping theballoon catheter; and (7) drying and then sterilizing the ballooncatheter.
 11. The method according to claim 10, wherein the meteringdispenser comprises at least one of a syringe, a syringe pump, ametering pipette, and an automatic metering system.
 12. The methodaccording to claim 10, wherein steps (2), (3), (4) and (5) occurconcomitantly.
 13. The method according to claim 10, wherein themetering dispenser comprises a dispensing tip, wherein the dispensingtip includes a tip and a flexible tail, and wherein in step (4) themethod further comprises dispensing the coating solution from themetering dispenser to the flexible tail and flowing the coating solutionfrom the flexible tail onto the surface of the medical device while themedical device is rotating and/or linearly moving.
 14. The methodaccording to claims 13, wherein the diameter of the opening of thedispensing tip ranges from 0.05 mm to 2 mm; the length of the dispensingtip ranges from 5 mm to 30 mm; and the length of the flexible tailranges from 5 mm to 30 mm.
 15. The method according to claim 10, whereinsteps (2), (3), (4) and (5) are repeated until a therapeuticallyeffective amount of the therapeutic agent in the coating is deposited onthe surface of the medical device.
 16. The method according to claim 10,wherein the total thickness of the coating layer is from about 0.1 to200 microns.
 17. The method according to claim 10, wherein theconcentration of the therapeutic agent in the coating layer is from 1 to20 μg/mm².
 18. The method according to claim 10, wherein the ballooncatheter is chosen from an over-the-wire and rapid exchange catheter,wherein the balloon catheter has a diameter from 1 mm to 40 mm, whereinthe balloon catheter has a length from 5 mm to 300 mm, and wherein theballoon catheter includes 0.014-inch, 0.018-inch and 0.035-inch wirecompatible lumen.
 19. The method according to claim 10, wherein themethod further comprises (8) drying the medical device aftersterilization.
 20. The method according to claim 19, wherein the ballooncatheter is sterilized with ethylene oxide, and wherein in step (8) theballoon catheter is dried under vacuum at about 0 to 100° C. forapproximately 2 to 56 hours.
 21. An apparatus for dispensing a coatingsolution on the surface of a medical device, the apparatus comprising: ametering dispenser; a coating solution storage container connected tothe metering dispenser; an apparatus that rotates a medical devicearound its longitudinal axis and moves the medical device back and forthin the direction of its longitudinal or transverse axis; and acontroller coordinating the metering dispenser and the apparatus. 22.The apparatus according to claim 21, wherein the metering dispensercomprises at least one of a syringe, a syringe pump, a metering pipette,and an automatic metering system.
 23. The apparatus according to claim21, wherein the apparatus concurrently rotates the medical device aroundits longitudinal axis at uniform tangential speed and translocates thedevice back and forth in a longitudinal direction at uniform frequency.24. The apparatus according to claim 21, further comprising a dispensingtip connected to the metering dispenser, wherein the dispensing tipcomprises a flexible tail connected to the tip.
 25. The method accordingto claims 24, wherein the diameter of the opening of the tip is from0.05 mm to 2 mm and the length of the tip is from 5 mm to 30 mm.
 26. Amethod for preparing a substantially uniform coated medical device,comprising: (1) preparing a first coating solution comprising a solvent,a therapeutic agent, and an additive; (2) loading a metering dispenserwith an amount of the first coating solution; (3) rotating the medicaldevice about the longitudinal axis of the medical device and/or movingthe medical device in a linear direction along the longitudinal ortransverse axis of the device; (4) dispensing the first coating solutionfrom the metering dispenser onto a surface of the balloon catheter andflowing the first coating solution on the surface of the medical devicewhile the balloon catheter is rotating and/or linearly moving; (5)evaporating the solvent, forming a substantially uniform first coatinglayer, and (6) repeating steps of (1), (2), (3), (4) and (5) with asecond coating solution, which is the same or different from the firstcoating solution until a desired number of coating layers are obtained.27. The method according to claims 1, 10, or 26, wherein the medicaldevice or a portion thereof has a continuous surface.
 28. The methodaccording to claim 1 or 10, wherein in step (5), the solvent isevaporated while the coating solution is moving at uniform speed,forming a substantially uniform dry coating layer over the surface ofthe medical device.
 29. The method according to claim 26, wherein themethod further comprises (7) sterilizing the medical device, and (8)drying the medical device after sterilization.
 30. The method accordingto claim 29, wherein in step (7) the medical device is sterilized withethylene oxide, and wherein in step (8) the medical device is driedunder vacuum at about 0 to 100° C. for approximately 2 to 56 hours. 31.A method for preparing a substantially uniform coating for medicaldevice, the method comprising: (1) preparing a coating solutioncomprising a solvent, a therapeutic agent, and an additive; (2) applyingthe coating solution to a medical device; (3) drying the coatingsolution, forming a coating layer; (4) sterilizing the medical device;and (5) drying the medical device after sterilization.
 32. The methodaccording to claim 31, wherein the medical device is a balloon catheter.33. The method according to claim 31, wherein in step (5), the medicaldevice is dried under vacuum at about 0 to 100° C. for approximately 2to 56 hours.